Background

Fogo selvagem (FS), or endemic pemphigus foliaceus (PF), is an autoimmune, organ-specific blistering disease, in which autoantibodies specific for desmoglein 1 may lead to acantholysis (ie, cell-cell detachment). Desmoglein 1 is a glycoprotein that belongs to the cadherin superfamily (ie, calcium adhesion molecules present in the desmosomal core). Other target antigens are also postulated to be relevant in the pathogenesis of pemphigus foliaceus.

Pemphigus foliaceus is characterized by clinical involvement of healthy-appearing skin that may blister when rubbed, a finding named after Dr Piotr Nikolsky[1] who initially described this finding.

Six types of pemphigus foliaceus exist. Fogo selvagem is an endemic form of pemphigus foliaceus and was formerly known as Brazilian pemphigus foliaceus because it was originally observed in specific river valleys of rural Brazil. It is also reported in Columbia; El Salvador; Paraguay; Peru; and, most recently, in Tunisia.[2]

The epidemiology, age distribution, and human leukocyte antigen (HLA) associations distinguish fogo selvagem from nonendemic pemphigus foliaceus. Fogo selvagem is Portuguese for wild fire. The description wild fire refers to photosensitivity and the common symptom of severe stinging or burning that occurs with ultraviolet (UV) exposure. In fact, in patients with pemphigus foliaceus, exposure to UV-B may induce acantholysis in uninvolved skin. Epidermal exposure to UV light may enhance autoantibody epidermal binding and preferential neutrophil adhesion, which can contribute to acantholysis in endemic pemphigus foliaceus.

Pierre Louis Alphee Cazenave, founder of the first journal dedicated entirely to dermatology, inserted into this journal the first description of pemphigus foliaceus in 1844 in a 47-year-old woman who consulted him at l'Hopital Saint Louis in Paris for a generalized eruption of several years duration.

Bites of black flies, in particular Simulium nigrimanum, may initiate this disorder, possibly due to salivary proteins that contain pharmacologically active compounds.[3]

Pathophysiology

The precise etiology is unknown, but immunogenetic, immunologic, and environmental factors contribute to its pathogenesis.[4] It may be due to a pathogenic IgG4 response triggered by hematophagous insect bites.[5] A 15-year surveillance of the Limao Verde Amerindian reservation in Brazil has elucidated a preclinical stage linked with IgM anti-Dsg1, IgE, and non-IgG4 autoantibodies against Dsg1 transitioning over years into fogo selvagem with the rise of pathogenic IgG4 anti-Dsg1 autoantibodies. The concept of antigenic mimicry in people genetically predisposed may be pivotal.[6]

Immunogenetic factors

A strong association between fogo selvagem and class II HLA antigens exists. In one study, 37 (88%) of 42 patients with fogo selvagem had one or both of the HLA DR1 and DR4 genes, whereas these genes were evident in only 22 (34%) of the 64 control subjects. The HLA-DR1-Dw20 (DRB1*0102) gene is related to susceptibility to fogo selvagem, whereas absence of the HLA-DQw2 (DQB1*0201) allele is linked with resistance. Not surprising, familial cases have been described.

A common epitope in the third hypervariable (positions 67-74) of the DRB1 gene is involved in susceptibility to fogo selvagem. It seems that healthy family members of patients with fogo selvagem have the dominant allele HLA-DQw2, which may be protective. Thus, susceptibility and resistance haplotypes may exist in people at risk for fogo selvagem.

Epidemiologic findings indicate that peasants exposed to black fly bites are 4.7 times more likely to develop fogo selvagem than those who were not exposed, as indicated by the odds ratio. A recent study performed at an Amerindian reservation in Mato Grosso do Sul, Brazil, revealed the predominance of a certain black fly species, Simulium nigrimanum. A 2015 study suggested that IgE anti-LJM11 sand fly salivary antigen may facilitate the development of fogo selvagem.[9]

A sero-epidemiological study of the Terena reservation of Limao Verde, known to have a high prevalence and incidence of fogo selvagem, suggested that the environmental antigen or antigens triggering the autoimmune response in fogo selvagem may be linked to exposure to hematophagous insects.[10]

Epidemiological evidence shows outbreaks in Brazil occurring on the banks of rivers where there is mercury contamination from alluvium gold mining and deforestation.[11] A similarity has been observed to pemphigus induced by sulphydryl (SH-) drugs. Thus, chronic methyl mercury poisoning may trigger the onset of fogo selvagem.

Immunologic factors

In the 1960s, the presence of anti–immunoglobulin G (IgG) circulating autoantibodies and in situ autoantibodies was described in patients with fogo selvagem. These autoantibodies were detected by means of indirect and direct immunofluorescence (IF), and intracellular staining was demonstrated within the epidermis. The autoantigen related to EPF is desmoglein 1, a 160-kd glycoprotein of the desmosomal core, targeted by in situ and circulating IgG autoantibodies, mainly of the IgG4 subclass.[8]

The IgG fraction from fogo selvagem was shown to be pathogenic by means of passive transfer in BALB/c mice. These animals develop the clinical, histologic, and immunologic features of the human disease within 24 hours after the intraperitoneal injection of human IgG. The predominant IgG subclass in fogo selvagem is IgG4.

Fogo selvagem is mediated by pathogenic antibodies to the EC1-2 domains of desmoglein-1.[12] A preclinical phase has been described with antibodies to only EC5. One hypothesis is that a component of insect vector saliva triggers an antibody response to EC-5. In susceptible individuals, a response to the EC1-2 domains may subsequently develop by epitope spreading with development of fogo selvagem. Inflammatory cytokines and apoptosis are also involved.[13]

Its etiology is unknown, but blister formation appears to be mainly IgG4 mediated. The anti-Dsg1 response in fogo selvagem is probably initiated by sensitization to an environmental allergen, with cross-reactive IgE, IgM, and pathogenic IgG4 anti-Dsg1 responses as their serological markers.[14] However, the LJM11 salivary protein of the sandfly is recognized by fogo selvagem antibodies.[15] Thus, insect bites provide salivary antigens that initiate a cross-reactive IgG4 antibody response in genetically susceptible individuals, likely to induce fogo selvagem. Accordingly, both desmoglein-1 autoantigen and LJM11 sand fly salivary gland antigen may provide the first antigenic stimulants for the IgG4 autoimmune responses seen in fogo selvagem.[16] Higher CD59 transcriptional levels may be related to susceptibility, particularly in women.[17]

Burning sensation

The intense cutaneous burning sensation with this disease was evaluated in testing for neural autoreactivity in patients affected by a new variant seen in Colombia. Autoreactivity to neural structures, mechanoreceptors, nerves, perineural cell layers of the arachnoid envelope around the optic nerve, brain structures, and to neuromuscular spindles was detected, with antibodies also colocalized with desmoplakins 1 and 2. These findings may explain the "burning sensation."[18]

Epidemiology

Frequency

The incidence of pemphigus foliaceus varies depending on the population studied. Pemphigus foliaceus is rare and sporadic worldwide. In contrast to pemphigus vulgaris, no predominance of pemphigus foliaceus exists in Jews and people of Mediterranean descent. This endemic variety of pemphigus foliaceus occurs with a high frequency in central and southwestern Brazil and in Colombia. The Terena reservation in Brazil, a recently identified focus, has a prevalence of 3.4% of the population. In endemic regions of Brazil, as many as 50 cases per million persons per year are seen. An endemic focus has been found in Tunisia.[2] Other foci may be present in the Maghreb; one case was described in Morocco.

In El Salvador, a similar female and age predisposition may also be present. An outbreak was described in 18 men and 3 women in rural Columbia. All were mestizos with an average age of 44 years (range, 22-82 y). Five were relatives. Most worked as farmers or gold miners.[19]

In Brazil, patients with fogo selvagem typically reside within 10-15 km of a river or stream, usually in the path of prevailing winds, as one might anticipate with a flying vector. The most likely candidate is a particular black fly, S nigrimanum, the predominant fly species in endemic but not in nonendemic regions in Brazil.

Data suggest patients with fogo selvagem in Peru share epidemiological, clinical, and immunological characteristics with those seen in Brazil and Colombia.[20]

Race

Pemphigus foliaceus is described in persons of all races. In contrast to pemphigus vulgaris, no predominance of pemphigus foliaceus exists in Jews and people of Mediterranean descent.

The role of genetic factors is evident in fogo selvagem, which is strongly associated with some HLA-DRB1 haplotypes, including DRB1*0404, DRB1*1402, DRB1*1406, and DRB1*1401. In France, persons with DRB1*0102 and DRB1*0404 have an increased risk for pemphigus foliaceus.

Sex

In general, the prevalence of fogo selvagem in men and women is about equal. However, in the Sousse region of Tunisia, an overwhelming predominance of women seem to be affected.[21]

An increased incidence of pemphigus foliaceus was noted in Tunisian women (6.6 cases per million per year), whereas in Western Europe the incidence of pemphigus foliaceus is about 0.5-1 case per million women per year. The annual incidence of endemic pemphigus foliaceus among women in the Sousse region of Tunisia peaks at 15.5 cases per million women aged 25-34 years. In El Salvador, a similar female and age predisposition may also be present. However, an outbreak was described in 18 men and 3 women in rural Columbia; this male predominance is impressive.

Age

The mean patient age of onset of pemphigus foliaceus is approximately 50-60 years. However, pemphigus foliaceus can occur in individuals of any age, from infancy onward. Fogo selvagem affects children and young adults. Fogo selvagem does not seem to cause neonatal fogo selvagem in children of mothers with fogo selvagem.

Fogo selvagem occurs in children and young adults and in their genetically related family members. The mean patient age is about 20-30 years.

The incidence of endemic pemphigus foliaceus among women in the Sousse region of Tunisia peaks in those aged 25-34 years. The incidence in genetically related family members does not appear to be increased.

In El Salvador, a similar age predisposition may be also present. However, in an outbreak in rural Columbia, the average patient age was 44 years (range, 22-82 y).

The average age of Peruvian patients was 31.4 years, with 55% of them being men.[22]

Prognosis

With therapy, the prognosis is good. Most patients respond well.

In young patients with fogo selvagem, the characteristics of stunted growth and diffuse cutaneous exfoliation are noteworthy. In patients with poorly controlled fogo selvagem, growth is arrested; this is alleviated by treatment.

This disorder affects young people in their prime, disrupting their academic and vocational pursuits. Personality changes may be manifested by blunted affect.

Azoospermia is described in adults who had fogo selvagem as children; however, some of the drugs used to treat this disease may also be associated with azoospermia.

History

Patients may describe the burning sensation for which the disorder is named. Bullae usually begin on the head, neck, and trunk in a seborrheic distribution. Patients may experience an intense burning or itching sensation.

Physical Examination

The clinical features of fogo selvagem are identical to those in the classic form of pemphigus foliaceus (Cazenave). The primary cutaneous lesions are superficial vesicles or blisters that rupture easily and leave superficial erosions.

The Nikolsky sign (ie, epidermal detachment after pressure on perilesional and nonlesional skin) usually is spread acrally. The Nikolsky sign emphasizes that physical trauma can shear the pathologic epidermis in pemphigus foliaceus to produce clinical lesions. The erosions can become numerous and have a tendency to generalize. Note the image below.

View Image

Generalized form with blisters and crusts on the trunk.

In contrast to pemphigus vulgaris, pemphigus foliaceus involves little or no involvement of the mucous membranes. UV exposure may enhance lesions or trigger their development.

Localized or generalized forms exist. Generalized forms may evolve into exfoliative erythroderma and lead to death (rare). Occasionally, extensive exfoliative erythroderma develops. Hyperpigmented or verrucous lesions may be observed in the course of the disease.

The primary lesions are small superficial blisters. These flaccid bullae are difficult to find because they are transient and transform into erosions.

The lesions tend to appear on the central trunk and face (ie, face, scalp, upper trunk) in a distribution similar to that of seborrheic dermatitis. Sometimes, atrophic changes of the nails and hair are evident. Burning and local pain may occur with the erosions. In some patients, a herpetiform variant is also observed.

Some patients with pemphigus foliaceus have the initial features of pemphigus herpetiformis. In Tunisia, this feature occurs in 35% of patients with endemic pemphigus foliaceus.

A variant of endemic pemphigus foliaceus in Colombia, South America is characterized by palms and soles that have an edematous texture and mild hyperkeratosis in addition to the blisters on nonglabrous skin.[25]

Causes

The precise etiology of fogo selvagem is unknown. Familial cases are reported.

Fogo selvagem is endemic in certain areas of Brazil and in other parts of Latin America. Epidemiologic studies indicate that peasants exposed to black fly bites are 4.7 times more likely to have fogo selvagem than those who were not exposed, as indicated by the odds ratio. One study performed at an Amerindian reservation in Mato Grosso do Sul, Brazil, revealed the predominance of a certain black fly species, S nigrimanum. In 1967, Beutner et al[23] first reported the presence of anti-IgG circulating autoantibodies or in situ autoantibodies in patients with fogo selvagem. Herpes simplex virus 1 and cytomegalovirus may be associated with pemphigus vulgaris, but are not associated with pemphigus foliaceus disease.[24]

Complications

Fogo selvagem itself and its therapy may both cause difficulties for the patient. The major complication of fogo selvagem is impetigo. Secondary fungal infections, Kaposi varicelliform eruption, scabies, and disseminated strongyloidiasis may occur.

Other complications reported in patients with fogo selvagem include dwarfism, azoospermia, dermatophytosis, warts, and Norwegian scabies. These complications may be related to long-term corticosteroid treatment.

In Peru, complications such as pyodermitis and pyelonephritis were found to occur during treatment, with increased risk in those noncompliant with treatment and in those having the generalized clinical form.[22] Residing in a rural area may also be a risk factor for complications.

Laboratory Studies

Indirect IF testing of the patient's serum: Intercellular fluorescence in the epidermis (anti-IgG autoantibodies) is observed. Often, a positive relationship between the intercellular fluorescence and the activity of the disease exists.[27] Direct IF of a biopsy sample of perilesional skin: Intercellular fluorescence in the epidermis (anti-IgG or anti-C3 autoantibodies) is observed.

With immunoblotting, epidermal extracts have reactivity against desmoglein 1 substrate (160 kd in 33% of the cases).

Immunoprecipitation with the recombinant desmoglein 1. Lane 1 is the result in normal human serum. Lanes 2-7 are findings in sera from patients with f....

The immunoglobulin M antidesmoglein-1 response appears to distinguish Brazilian pemphigus foliaceus (fogo selvagem) from other forms of pemphigus. However, immunoglobulin M antidesmoglein-1, which is common in fogo selvagem patients in their native environment and uncommon in other pemphigus phenotypes, is also infrequent in fogo selvagem patients who migrate to urban areas.[28]

With enzyme-linked immunosorbent assay (ELISA), rDsg1-His has 96% positivity with fogo selvagem sera. The sensitivity of indirect IF and ELISA in detecting intercellular antibodies in fogo selvagem was studied.[29] ELISA (rDsg1) was found to be slightly more sensitive than indirect IF in detecting circulating autoantibodies. However, no test is 100% accurate in differentiating fogo selvagem from pemphigus vulgaris. In this study, 4 (12%) of 32 patients with fogo selvagem (cutaneous diseases only) also had desmoglein-3 antibodies.

The development of an IgG4-based predictor of fogo selvagem may be possible.[30] Identifying individuals at increased risk or those with preclinical fogo selvagem may facilitate disease prevention, and it may assist in identifying the etiological agent or triggering factors.

Histologic Findings

Pemphigus foliaceus begins with acantholysis of the upper epidermis, which often results in a subcorneal cleft. The subcorneal cleft usually enlarges and detaches without bullae formation, although a bulla may form, with acantholysis at both the roof and the floor.

More established lesions may have acanthosis and mild-to-moderate papillomatosis. Hyperkeratosis and parakeratosis may also be evident, with dyskeratotic cells within the granular layer. A mild dermal lymphocytic infiltrate, often associated with the presence of eosinophils, is observed.

Medical Care

Mario Fonzari pioneered the use of cortisone and thereby revolutionized treatment of this disorder, substantially reducing mortality.[31, 32] For patients with severe fogo selvagem, systemic corticosteroid therapy is the treatment of choice. Prednisone (1 mg/kg body weight) is administered as a single daily morning dose until blister formation ceases or the Nikolsky sign disappears. After initial control is achieved, the prednisone dose is reduced to about half the initial dose. This reduction is followed by slow tapering to the minimal effective maintenance dose over weeks to months. Adjuvant therapy includes the use of immunosuppressants such as azathioprine (1-2 mg/kg body weight until lesions clear; with slow tapering of dose), cyclophosphamide (100-200 mg qd, with a reduction to a maintenance dose of 50-100 mg qd), and mycophenolate mofetil (1.5-3 g/d).

Therapy for fogo selvagem is usually less aggressive than that of pemphigus vulgaris because of the lower morbidity and mortality rates. In patients with limited involvement, topical glucocorticosteroids may be sufficient. In more extensive cases, an aggressive treatment (similar to that of pemphigus vulgaris) is necessary; this treatment includes systemic corticosteroids and immunosuppressants. In some cases, coadministration of anti-inflammatory agents such as gold, antimalarials, sulfones, or antibiotics may be useful. In some patients with pemphigus foliaceus, nicotinamide 1.5 g/d and tetracycline 2 g/d is reported to be useful.

Topical treatment with antibiotics and corticosteroids is beneficial. Potent corticosteroid ointments may be effective with long-lasting lesions.

In some patients, photoprotection may be helpful because UV-B light may trigger acantholysis and cause the disease to flare.

Antiacantholytic therapies in patients with pemphigus, using cholinomimetics, indicates that cholinergic drugs may be a promising approach for fogo selvagem.[33]

Plasmapheresis is another therapeutic option. Plasmapheresis is indicated for patients with poorly controlled disease or those with high circulating autoantibody titers. In some patients, this therapy may decrease the autoantibody titers and favorably influence the clinical outcome, especially in otherwise therapy-resistant pemphigus foliaceus. Plasmapheresis should be used in conjunction with daily cyclophosphamide treatment to reduce a predictable rebound increase in autoantibody synthesis. Potential complications, including the need for maintaining venous access, a bleeding tendency, electrolyte shifts, pulmonary edema, fever, chills, hypotension, and septicemia, should be considered.

Prevention

In endemic areas, measures to minimize exposure to biting flies and other insect vectors are appropriate. These measures include the use of insecticides, protective clothing, and insect screens. In some patients, photoprotection may be helpful because UV-B light may trigger acantholysis and cause the disease to flare.

Long-Term Monitoring

Frequent clinical follow-up is required in patients with active disease. Patients should be monitored for disease progression, development of complications such as infections, and compliance with and complications of their medications. Some clinicians monitor indirect IF titers to gauge the response to therapy; however, this practice is not universal. Patients taking long-term steroids and/or immunosuppressants should be appropriately followed up and monitored. The lowest possible dose of steroids and immunosuppressants should be used to minimize the potential for systemic toxicities.

Be aware of bacterial, viral, or fungal secondary infections and infestations. Disseminated strongyloidiasis is reported.

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli. Corticosteroids are used to treat inflammatory dermatosis responsive to steroids. They decrease inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.

Cyclophosphamide (Cytoxan, Neosar)

Clinical Context:
Cyclophosphamide is an immunosuppressive agent. It may be used as monotherapy or as a steroid-sparing agent. Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, its mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Class Summary

Dapsone (Avlosulfon)

Clinical Context:
Dapsone is used to control dermatologic symptoms of dermatitis herpetiformis. It can be used for patients with pemphigus, and it may be the drug of choice for pemphigus herpetiformis and IgA pemphigus. Dapsone may be provided as monotherapy or in combination with systemic steroids and immunosuppressants.

Class Summary

Dapsone is bactericidal and bacteriostatic against mycobacteria. The mechanism of action is similar to that of sulfonamides in which competitive antagonists of PABA prevent the formation of folic acid, inhibiting bacterial growth.

Class Summary

Author

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Jeffrey P Callen, MD, Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Biogen/IDEC (Discussion of Drug reactions in relationship to an agent for Multiple Sclerosis)<br/>Received income in an amount equal to or greater than $250 from: Abbvie; Lilly; Argenx; Amgen <br/>Received honoraria from UpToDate for author/editor; Received honoraria from JAMA Dermatology for associate editor; Received royalty from Elsevier for book author/editor; Received dividends from trust accounts, but I do not control these accounts, and have directed our managers to divest pharmaceutical stocks as is fiscally prudent from Stock holdings in various trust accounts include some pharmaceutical companies and device makers for i inherited these trust accounts; for: Celgene; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen.

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Naked Biome<br/>Received income in an amount equal to or greater than $250 from: Elsevier; WebMD<br/>StatPearls; Editor.

Additional Contributors

Disclosure: Received none from Amgen for consultant & investigator; Received none from Novartis for consultant & investigator; Received none from Pfizer for consultant & investigator; Received none from Celgene Corporation for consultant & investigator; Received none from Clinuvel for consultant & investigator; Received none from Eli Lilly & Co. for consultant & investigator; Received none from Janssen Ortho Biotech for consultant & investigator; Received none from LEO Pharmaceuticals for consultant & inves.

Generalized form with blisters and crusts on the trunk.

Immunoprecipitation with the recombinant desmoglein 1. Lane 1 is the result in normal human serum. Lanes 2-7 are findings in sera from patients with fogo selvagem. Lanes 2-7 show the reaction of the sera against the extracellular domain of desmoglein 1.

Generalized form with blisters and crusts on the trunk.

Immunoprecipitation with the recombinant desmoglein 1. Lane 1 is the result in normal human serum. Lanes 2-7 are findings in sera from patients with fogo selvagem. Lanes 2-7 show the reaction of the sera against the extracellular domain of desmoglein 1.